Mitochondria are unique cellular organelles that contain their own DNA, distinct from the nuclear genome. Mitochondrial DNA (mtDNA) mutations affect all tissues, but postmitotic tissues, such as muscle and brain, are affected more severely, most likely due to their increased energy requirement. MERF (myoclonus epilepsy with ragged-red fibers) and MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) are two maternally inherited mitochondrial diseases associated with point mutations in two different mtDNA- encoded tRNA genes. The two disorders present with distinct clinical phenotypes, but both feature developmental delay, mental retardation, mitochondrial proliferation in muscle, and severe deficiencies in respiratory chain function. We propose to study intergenomic interactions between mitochondrial harboring two populations of mtDNAs containing each of two different point mutations associated with MERRF (A8344G), in order (1) to determine if genetic complementation between the two genomes can restore normal respiratory chain function in postmitotic muscle, and (2) to evaluate other cellular factors, such as mitochondrial movement and shape, and the role of cytoskeletal proteins, that might play a role in interorganellar and intergenomic interactions. We also plan to study the unique vascular pathology associated with MELAS, using a vascular smooth muscle cell line (VSM) that has been repopulated with the A3243G mutation. Clinically, MELAS patients have severe lactic acidosis. In this regard, we also propose to study the regulation of glycolysis and glucose oxidation in these cells, and to determine if dichloroacetate (DCA) can alleviate the biochemical abnormalities, if present. The results of this proposed study will help us to devise strategies for restoring normal oxidative function in post-mitotic muscle, either biochemically or by genetic interaction.